ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.4G>T (p.Gly2Cys) (rs372082751)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000483125 SCV000570277 uncertain significance not provided 2016-05-09 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.4G>T at the cDNA level, p.Gly2Cys (G2C) at the protein level, and results in the change of a Glycine to a Cysteine (GGC>TGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Gly2Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RAD51D Gly2Cys occurs at a position where amino acids with properties similar to Glycine are tolerated across species and is located in the region that preferentially binds ssDNA (Kim 2011, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. This variant occurs in a conserved nucleotide in the Kozak consensus sequence and therefore may impact protein translation; however, in the absence of functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether RAD51D Gly2Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV001055029 SCV001219393 uncertain significance Breast-ovarian cancer, familial 4 2019-02-25 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 2 of the RAD51D protein (p.Gly2Cys). The glycine residue is weakly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is present in population databases (rs372082751, ExAC 0.002%). This variant has not been reported in the literature in individuals with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 421161). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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